Cirrhosis is the tenth leading cause of deaths in the United States in males and the twelfth leading cause of death in females. Non-alcoholic fatty liver disease (NAFLD) may account for the majority of patients who have cryptogenic cirrhosis. The majority of cases of NAFLD are related to metabolic syndrome which includes obesity, type 2 diabetes mellitus, and hypertriglyceridemia. According to retrospective data approximately 3% of the American people have NASH (non-alcoholic steatohepatitis). Our long-term consequence of disease progression to cirrhosis will impose great challenges to the American people. The long-term goal is to elucidate the molecular basis for liver fibrosis, which can ultimately lead to cirrhosis. This proposal meets the mission of the action plan for liver disease research. In the prior funding period, we have convincingly demonstrated that leptin, an adipocytokine produced primarily by white adipose tissue, is a profibrogenic cytokine in the development of hepatic fibrosis. Leptin augments net production of extracellular matrix (ECM) by increasing hepatic stellate cell proliferation (HSC), increases type I collagen synthesis and increases tissue inhibitor of metalloproteinase 1 (TIMP-1);and impedes a timely death of HSCs by strongly inhibiting apoptosis. The overall goal of the current proposal is to demonstrate the biological consequences of leptin and adiponectin as novel modulators of liver fibrosis. We hypothesize that adiponectin is protective against leptin-induced hepatic fibrosis in vitro and in vivo by AMPK blockade of Jak2/Stat3 signal transduction. Three specific aims have been designed to test this hypothesis. (1). To dissect the molecular pathway whereby adiponectin-activated AMPK impedes Jak2/Stat3 signal transduction, and determine whether leptin enhanced signaling via the PI-3K/Akt and extracellular regulated kinase (Erk, p44/p42), and p38 pathways are directly inhibited as assessed by HSC proliferation and apoptosis.(2).To demonstrate that adiponectin antagonizes leptin's action in the rat HSC by reducing net production of extracellular matrix (ECM) molecules, decreasing the transcriptional activity of tissue inhibitor of metalloproteinase I (TIMP-1) and increasing the functional activity of matrix metalloproteinases (MMPs) that are known to degrade type I collagen. (3). To employ adiponectin knockout (Ad KO) mice to elucidate in vivo how adiponectin modulates the biological effect of leptin in hepatic fibrogenesis as assessed by carbon tetrachloride (CCl4) exposure. PUBLIC HEALTH RELEVANCE: Cirrhosis is a major cause of death in the United States. A primary focus of the laboratory is to unlock molecular switches that regulate the scar tissue known to cause this chronic liver disease. We have observed that two hormones associated with fat metabolism -leptin and adiponectin- can alter the dynamics of scar formation in the liver as well as in the hepatic cells associated with this disease in humans. The project seeks to determine whether adiponectin can act as a protector from the harmful effects of leptin in liver fibrosis.